With the use of family study methods and assessments by "blinded" raters, we tested hypotheses about patterns of familial association between DSM-III attention deficit disorder (ADD) and affective disorders (AFFs) among first-degree relatives of clinically referred children and adolescents with ADD (73 probands, 264 relatives) and normal controls (26 probands, 92 relatives). Among the 73 ADD probands, 24 (33%) met criteria for AFFs (major depression, n = 15 [21%]; bipolar disorder, n = 8 [11%]; and dysthymia, n = 1 [1%]). After stratification of the ADD sample into those with AFFs (ADD + AFF) and those without AFF (ADD), familial risk analyses revealed the following: (1) the relatives of each ADD proband subgroup were at significantly greater risk for ADD than were relatives of normal controls; (2) the age-corrected morbidity risk for ADD was not significantly different between relatives of ADD and ADD + AFF (27% vs 22%); however, these two risks were significantly greater than the risk to relatives of normal controls (5%); (3) the risk for any AFF (bipolar disorder, major depressive disorder, or dysthymia) was not significantly different between relatives of ADD probands and ADD + AFF probands (28% and 25%), but these two risks were significantly greater than the risk to relatives of normal controls (4%); (4) ADD and AFFs did not cosegregate within families; (5) there was no evidence for nonrandom mating. These findings are consistent with the hypothesis that ADD and AFFs may share common familial vulnerabilities.

OBJECTIVE: To examine the prevalence, characteristics, and correlates of mania among referred children aged 12 or younger. Many case reports challenge the widely accepted belief that childhood-onset mania is rare. Sources of diagnostic confusion include the variable developmental expression of mania and its symptomatic overlap with attention-deficit hyperactivity disorder (ADHD).METHOD: The authors compared 43 children aged 12 years or younger who satisfied criteria for mania, 164 ADHD children without mania, and 84 non-ADHD control children.RESULTS: The clinical picture was fully compatible with the DSM-III-R diagnosis of mania in 16% (n = 43) of referred children. All but one of the children meeting criteria for mania also met criteria for ADHD. Compared with ADHD children without mania, manic children had significantly higher rates of major depression, psychosis, multiple anxiety disorders, conduct disorder, and oppositional defiant disorder as well as evidence of significantly more impaired psychosocial functioning. In addition, 21% (n = 9) of manic children had had at least one previous psychiatric hospitalization.CONCLUSIONS: Mania may be relatively common among psychiatrically referred children. The clinical picture of childhood-onset mania is very severe and frequently comorbid with ADHD and other psychiatric disorders. Because of the high comorbidity with ADHD, more work is needed to clarify whether these children have ADHD, bipolar disorder, or both.

They had started looking at the association between ADD and Affective Disorders, but were now honing in on the existence and prevalence of Mania and Bipolar Disorders in Childhood. And they weren’t the only ones:

Bipolar disorder (BPD), probably the most prevalent psychotic disorder in adults, has been relatively neglected or controversial in children and adolescents over the past century. We reviewed the literature on early-onset BPD. Estimates of prevalence, particularly before puberty, are limited by historical biases against pediatric mood disorders and by formidable diagnostic complexity and comorbidity. Although clinical features of pediatric and adult BPD have similarities, pediatric cases probably cannot be defined solely by features characteristic of adult cases. Onset was before age 20 years in at least 25% of reported BPD cases, with some increase in this incidence over the past century. Pediatric BPD is familial more often than is adult-onset BPD, may be associated with a premorbid cyclothymic or hyperthymic temperament, and can be precipitated by antidepressant treatment. Pediatric BPD episodes frequently include irritability, dysphoria, or psychotic symptoms; they are commonly chronic and carry high risks of substance abuse and suicide. BPD is often recognized in adolescents, but the syndrome or its antecedents are almost certainly underrecognized and undertreated in children. Controlled studies of short- and long-term treatment, course, and outcome in this disorder remain strikingly limited, and the syndrome urgently requires increased clinical and scientific interest.

There were some other things going on around that time. The DSM-IV had just come out, softening the Bipolar criteria [Bipolar II] and there had been the First International Conference on Bipolar Disorder. The first Atypical Antipsychotic, Risperal had just been approved for Adult Schizophrenia. We know that Janssen had asked Dr. Biederman to study Risperdal in kids from a later internal email, but then bailed out on him:

We don’t know what he had proposed, but his areas of interest were ADHD and Pediatric Bipolar Disorders. Over the next three years, Biederman’s group published 16 papers on the subject of Bipolar Disorder in children and adolescents. This summary from his paper in a Biological Psychiatry devoted to Bipolar Disorders makes his view of Bipolar Disorder in kids clear:

… The symptomatic overlap and co-occurrence of mania with ADHD has produced debate as to whether these children have ADHD, mania, or both. Despite this debate, many clinicians recognize that a substantial minority of children suffer from an extraordinarily severe form of psychopathology associated with extreme irritability, violence, and incapacitation that is highly suggestive of mania. Clarifying the diagnoses of these very ill children would have substantial clinical implications.

The emerging literature indicates that mania can be identified in a substantial number of referred children using systematic assessment methodology. Thus, this disorder may not be as rare as previously considered. Children with mania frequently demonstrate an atypical picture by adult standards, with a chronic course, severely irritable mood, and a mixed picture with depressive and manic symptoms co-occurring. Most children with childhood-onset mania may also have ADHD, which requires additional treatment. Initial clinical evidence suggests that atypical neuroleptics may play a unique therapeutic role in the management of such youth. The high levels of comorbidity with other disorders is common, further requiring the cautious use of a combined pharmacotherapy approach. More research is needed to build a scientific foundation for the notion that pediatric mania is a unique developmental subtype of bipolar disorder.

What happened in that second half of the 1990s is that they created a new diagnosis – Pediatric Bipolar Disorder. Looking at these articles [Faedda et al and Biederman et al] or at the COBY Study [started right around this time], Bipolar Disorder in children was becoming a common diagnostic term, but the diagnostic criteria bore little resemblance to the familiar symptom complexes from the Manic Depressive Illness of old. It was something new masquerading as something old [or vice versa]. These kids weren’t euphoric, they were irritable. They didn’t have discrete episodes like the classic cases, in fact many didn’t have episodes at all – they were always afflicted. In 2010, Dr. Allen Frances, who had been in charge of the DSM-IV revision in 1994 had this to say looking back on what happened:

Mark Twain observed that "the past may not repeat itself, but it sure does rhyme." An unfortunate rhyme in psychiatric history is the recurrence of fad diagnoses. Childhood Bipolar Disorder is the most dangerous current bubble, with a remarkable forty-fold inflation in just one decade. Painful experience has taught me a lot about diagnostic fads. As Chair of the DSM-IV Task Force (which prepared the official manual of psychiatric diagnosis), I bear partial responsibility for two other false "epidemics" – of attention deficit and autistic disorders. But the childhood bipolar fad did not arise from anything we wrote into DSM IV. Instead, it started because clinicians ignored the DSM-IV definition in favor of a new and largely untested idea that Bipolar Disorder presents very differently in children. Most kids who now get the diagnosis have non-episodic temper outbursts and irritability – not the classic mood swings between mania and depression. The boundaries of childhood Bipolar Disorder have pushed far into unfamiliar territory, to label kids who previously received other diagnoses…

To become a fad, a psychiatric diagnosis requires three preconditions: a pressing need, an engaging story, and influential prophets. The pressing need arises from the fact that disturbed and disturbing kids are very often encountered in clinical, school, and correctional settings. They suffer and cause suffering to those around them–making themselves noticeable to families, doctors, and teachers. Everyone feels enormous pressure to do something. Previous diagnoses [especially conduct or oppositional disorder] provided little hope and no call to action. In contrast, a diagnosis of childhood Bipolar Disorder creates a justification for medication and for expanded school services. The medications have broad and nonspecific effects that are often helpful in reducing anger, even if the diagnosis is inaccurate. The "epidemic" of childhood Bipolar Disorder fed off the engaging storyline that it: 1)is extremely common; 2) was previously greatly under-diagnosed; 3) presents differently in children because of developmental factors; 4) can explain the variety of childhood emotional dysregulation; and, 5) has diverse presenting symptoms [e.g., irritability, anger, agitation, aggression, distractibility, hyperactivity, and conduct problems].

The prophets were "thought leading" researchers who encouraged child psychiatrists to ignore the standard bipolar criteria and instead to make the diagnosis in a free-form, over-inclusive way. Then enter the pharmaceutical industry – not very good at discovering new drugs, but extremely adept at finding new markets for existing ones. The expanded reach of childhood Bipolar Disorder created an inviting target. The bandwagon was further advanced by advocacy groups, the media, the internet, and numerous books aimed at suffering parents. The massive over-diagnosis of childhood bipolar disorder comes with large costs. Inappropriately diagnosed children are often treated with medications that are unnecessary and potentially quite [especially those that cause rapid and substantial weight gain, increasing the risk of diabetes and possibly reducing life span]…

In a couple of earlier posts, I admitted to the existence of Childhood Bipolar Disorder [bipolar kids: COBY (Course and Outcome of Bipolar Youth)…, bipolar kids: my take from COBY…]. But I totally agree with Dr. Frances that the Biederman-led movement to broaden the category to call all kinds of difficult and disruptive children Bipolar had little to no scientific basis. It felt like a rationalization to use the new atypical antipsychotics to control difficult behavior-disordered kids – a trick. So it’s no big surprise that in 1999, Biederman and his group published this chart review:

OBJECTIVE: To investigate the effectiveness and tolerability of the atypical neuroleptic risperidone in the treatment of juvenile mania.METHOD: This is a retrospective chart review of outpatients with the diagnosis of bipolar disorder (DSM-IV) treated with risperidone at a university center. Response to treatment was evaluated using the Clinical Global Impression Scale (CGI) with separate assessments of mania, psychosis, aggression, and attention-deficit/hyperactivity disorder (ADHD).RESULTS: Twenty-eight youths (mean +/- SD age, 10.4 +/- 3.8 years) with bipolar disorder (25 mixed and 3 hypomanic) who had been treated with risperidone were identified. These children received a mean dose of 1.7 +/- 1.3 mg over an average period of 6.1 +/- 8.5 months. Using a CGI Improvement score of < or = 2 (very much/much improved) to define robust improvement, 82% showed improvement in both their manic and aggressive symptoms, 69% in psychotic symptoms, but only 8% in ADHD symptoms.CONCLUSIONS: Although limited by its retrospective nature, this study suggests that risperidone may be effective in the treatment of manic young people and indicates the need for controlled clinical trials of risperidone and other atypical neuroleptics in juvenile mania.

Even in my day [70s-80s], the Antipsychotics were only used in Affective disorders acutely, to "bring down" agitated Manic Patients or to treat psychosis in the height of Manic or Depressive episodes. I know of no maintenance use back then [nor can I find much about it PubMed], so using Atypical Antipsychotics in Bipolar Disorders was something new, certainly new in kids. And even without knowing what we know today about what happened, at the turn of the last century there was plenty of reason to smell a rat [named pharma]. The articles had all the tell-tale phrases – "urgent public health problem" "emerging new treatments" "need for more research" – an all too familiar lingo that pointed down a well-traveled yellow brick road. And this time it didn’t lead to Oz, it lead to Harvard University. And the guy behind the curtain was Joseph Biederman…

I can’t keep up with your posts but I would like to say that there are more people working on early-onset bipolar than Joseph Biederman. It would be good to look at other authors, including some from outside the US.

My own opinion is that the more studies the better, because this has been an overlooked area of medicine. I also wish you “adult” psychiatrists and “child/adolescent” psychiatrists would talk to each other.